This is a 5 year proposal to develop powerful new methodologies -in psychiatric genetics. Specifically to: (1) incorporate measures of diagnostic-stability into the Single Major Locus Model to permit explicit modeling of diagnostic error and clinical heterogeneity in linkage analysis; (2) develop models for the simultaneous use of biochemical, or psychosocial measures, and indices of latent variables; (3) implement the multivariate analysis of quantitative and qualitative traits in nuclear families; (4) incorporate follow-up data into genetic models to allow for diagnostic evaluations at multiple points in time; (5) modify survival and logistic analyses for use in family data to incorporate variable age of onset and secular trends into genetic and linkage analyses; (6) perform a series of simulation experiments to evaluate different experimental designs for genetic studies in psychiatry; (7) develop efficient computer programs which implement these procedures; (8) apply these new techniques to a number of existing data sets, including studies of Affective Disorders and Alcoholism. Long term objectives are to develop realistic genetic and non-genetic transmission models of the familial distributions of psychiatric illness, develop tests of nosological hypotheses and resolve phenotypic heterogeneities, develop techniques to detect specific environmental and genetic factors, provide documented computer programs to the scientific community, and collaborate with others to study a broad spectrum of psychiatric and medical disorders. Methods include theoretical, computer implementation and simulation, and data analysis. First, theoretical issues in genetic epidemiology and linkage analysis will be resolved, these advances will then be extended and numerical techniques improved. Next, computer programs will be implemented and simulations used to assess operating characteristics. Finally, the methods will be applied to data. This research will enable the definition of more etiologically homogeneous subgroups of affected individuals, the characterization of specific modes of transmission, improved risk prediction, the discovery of relevant pre- morbid characteristics, and enhance the power of linkage analysis to detect abnormal genes.